Despite considerable research on gender differences in pain sensitivity, sex differences in pain modulation by opioid analgesics in humans have only recently been examined. We showed, in postoperative dental patients, that k (kappa)-partial agonist opioids produce significantly greater analgesia in females than in males. This finding was observed with three different opioid analgesics that are k-partial agonists: pentazocine, nalbuphine and butorphanol. In dose response studies performed during the current grant period, we further demonstrated that the greater analgesic potency in females for k- partial agonists may be at least partly due to the existence of a naloxone-sensitive anti-analgesia mechanism that predominates in males. Whereas due to this anti-analgesia a k-opioid (nalbuphine) produced greater pain than placebo in males, the addition of naloxone resulted in a markedly enhanced and prolonged analgesia in both genders. Recent evidence in animal models suggests that k-partial agonists may inhibit analgesia by their action at naloxone-sensitive s (sigma)-receptors, which could explain the anti-analgesic effects of k-opioid partial agonists. In previous experiments, we found that combining k- partial agonists with the alpha2-adrenergic agent, clonidine also enhances analgesia. The proposed experiments will identify the mechanism of the anti- analgesic action of the k-partial agonists. They will also determine optimal doses for the specific k-partial agonist (nalbuphine, butorphanol, pentazocine) naloxone combinations in other clinical settings, including repeated use in hospitalized post-surgical patients and patients with neuropathic pain. We will also explore gender and ethnic differences in analgesic responses resulting from k-opioids combined with the adjuvants known to interact with other neurotransmitter systems/mechanisms involved in pain modulation, that is, agents that act at a2- adrenergic receptors, and s-receptors. Finally, we will further characterize the opioid contribution to placebo analgesia. These studies will provide much-needed knowledge of gender differences in responses to opioid analgesics and should lead to gender- specific recommendations for more effective, better targeted pain therapy.